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Pingxiang Xu, Ying Liu, Liyun Wang, Yi Wu, Xuelin Zhou, Junhai Xiao, Jianquan Zheng, Ming Xue
To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [3 H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method...
February 13, 2019: Scientific Reports
Nabeel B Nabulsi, Daniel Holden, Ming-Qianq Zheng, Frederic Bois, Shu-Fei Lin, Soheila Najafzadeh, Hong Gao, Jim Ropchan, Teresa Lara-Jaime, David Labaree, Anupama Shirali, Lawrence J Slieker, Cynthia D Jesudason, Vanessa N Barth, Antonio Navarro, Nancy Kant, Richard E Carson, Henry Huang
The M1 muscarinic acetylcholine receptor (mAChR) plays an important role in learning and memory, and therefore is a target for development of drugs for treatment of cognitive impairments in Alzheimer's disease and schizophrenia. The availability of M1-selective radiotracers for positron emission tomography (PET) will help in developing therapeutic agents by providing an imaging tool for assessment of drug dose-receptor occupancy relationship. Here we report the synthesis and evaluation of 11 C-LSN3172176 (ethyl 4-(6-(methyl-11 C)-2-oxoindolin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate) in non-human primates...
February 7, 2019: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Ji Eun Kim, Woo Bin Yun, Mi Lim Lee, Jun Young Choi, Jin Ju Park, Hye Ryeong Kim, Bo Ram Song, Jin Tae Hong, Hyun Keun Song, Dae Youn Hwang
Constipation is an acute or chronic illness attributed to various causes, ranging from lifestyle habits to side effects of a disease. To improve the laxative effects of some traditional medicines, herbal mixtures of Liriope platyphylla, Glycyrrhiza uralensis, and Cinnamomum cassia (LGC) were evaluated for their mechanism of action and therapeutic effects in loperamide (Lop)-induced constipated Sprague Dawley rats by examining alterations in excretion parameters, histological structure, mucin secretion, and related protein levels...
February 6, 2019: Journal of Medicinal Food
Takayoshi Masuoka, Junsuke Uwada, Makiko Kudo, Hatsumi Yoshiki, Yuka Yamashita, Takanobu Taniguchi, Matomo Nishio, Takaharu Ishibashi, Ikunobu Muramatsu
Hippocampal cholinergic activity enhances long-term potentiation (LTP) of synaptic transmission in intrahippocampal circuits and regulates cognitive function. We recently demonstrated intracellular distribution of functional M1-muscarinic acetylcholine receptors (mAChRs) and neuronal uptake of acetylcholine (ACh) in the central nervous system. Here we examined whether endogenous ACh acts on intracellular M1-mAChRs following its uptake and causes cholinergic facilitation of hippocampal LTP. ACh esterase (AChE) activities and [3 H]ACh uptake was measured in rat hippocampal segments...
January 29, 2019: Neuroscience
Aaron D Gross, Jeffrey R Bloomquist
G-Protein-Coupled Receptors (GPCRs) are an underdeveloped target in the search for agrochemicals with octopamine receptors, a GPCR, being the target of a single insecticide/acaricide class (formamidines). The evolution of insecticide resistance has resulted in the need to identify new or underutilized targets for the development of agrochemicals, with the goal of controlling arthropod pests that affect agriculture or human and animal health. The insect cholinergic system has been a fruitful target for the development of insecticides/acaricides viz...
October 2018: Pesticide Biochemistry and Physiology
C E Covantes-Rosales, G A Toledo-Ibarra, K J G Díaz-Resendíz, G H Ventura-Ramón, M I Girón-Pérez
Nervous and immune systems maintain a bidirectional communication, expressing receptors for neurotransmitters and cytokines. Despite being well established in mammals, this has been poorly described in lower vertebrates as fishes. Experimental evidence shows that the neurotransmitter acetylcholine (ACh) regulates the immune response. In this research, we evaluated mRNA levels of muscarinic acetylcholine receptor (mAChR) in spleen mononuclear cells of Nile tilapia (Oreochromis niloticus) and compared the expression levels of immune cells with the brain...
January 22, 2019: Journal of Neuroimmunology
Tawit Suriyo, Sadudee Chotirat, Chirayu U Auewarakul, Karnjana Chaiyot, Orathai Promsuwicha, Jutamaad Satayavivad
Cholinergic receptors, such as α7-nicotinic acetylcholine receptor (α7-nAChR) and M3-muscarinic acetylcholine receptor (M3-mAChR), have been demonstrated to serve a significant role in the proliferation, differentiation and apoptosis of leukemic cells. However, the expression of these receptors in samples from patients with leukemia remains unclear. The present study aimed to determine the expression of M3-mAChR and α7-nAChR in the bone marrow or peripheral blood of 51 patients with leukemia, including acute myeloid leukemia (AML; n=33), acute lymphoblastic leukemia (ALL; n=13), and chronic myeloid leukemia (CML; n=5)...
January 2019: Oncology Letters
Ana Paula Ramos Costa, Brunno Rocha Levone, Anand Gururajan, Gerard Moloney, Alexandre A Hoeller, Cilene Lino-de-Oliveira, Timothy G Dinan, Olivia F O'Leary, Thereza Christina Monteiro de Lima, John F Cryan
The cholinergic system is one of the most important neurotransmitter systems in the brain with key roles in autonomic control and the regulation of cognitive and emotional responses. However, the precise mechanism by which the cholinergic system influences behaviour is unclear. Adult hippocampal neurogenesis (AHN) is a potential mediator in this context based on evidence, which has identified this process as putative mechanism of antidepressant action. More recently, post-transcriptional regulation by microRNAs is another candidate mechanism based on its involvement in the regulation of AHN and neurotransmission...
January 13, 2019: Behavioural Brain Research
Xiaoyun Deng, Akiko Hatori, Zhen Chen, Katsushi Kumata, Tuo Shao, Xiaofei Zhang, Tomoteru Yamasaki, Kuan Hu, Qingzhen Yu, Longle Ma, Gangqiang Wang, Lu Wang, Yihan Shao, Lee Josephson, Shaofa Sun, Ming-Rong Zhang, Steven Liang
Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M1 -M5 ) and are involved in the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Attributed to the promising clinical efficacy of xanomeline, an M1 /M4 -preferring agonist, in patients of schizophrenia and Alzheimer's disease, M1 - or M4 -selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of 11 C-labeled positron emission tomography (PET) ligands based on a validated M4 R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery...
December 27, 2018: ChemMedChem
Szymon Chowański, Joanna Pacholska-Bogalska, Grzegorz Rosiński
Synthetic insecticides are still widely used in plant protection. The main target for their action is the nervous system, in which the cholinergic system plays a vital role. Currently available insecticides have low selectivity and act on the cholinergic systems of invertebrates and vertebrates. Acetylcholine, a cholinergic system neurotransmitter, acts on cells by two types of receptors: nicotinic and muscarinic. In mammals, the role of muscarinic acetylcholine receptors (mAChRs) is quite well-known but in insects, is still not enough...
December 20, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Bao Trong Nguyen, Naveen Sharma, Eun-Joo Shin, Ji Hoon Jeong, Sung Hoon Lee, Choon-Gon Jang, Seung-Yeol Nah, Toshitaka Nabeshima, Yukio Yoneda, Hyoung-Chun Kim
Theanine (γ-glutamylethylamide), an amino acid in tea, is a putative neuroprotective and antioxidant compound capable of improving lifespan and cognitive function. Because we previously reported cognitive dysfunction in klotho mutant mice via down-regulation of janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3), M1 muscarinic cholinergic receptor (M1 mAChR), and ERK signaling, we, therefore, investigated whether self-administration of theanine affects memory dysfunction in response to klotho gene depletion in mice, and whether theanine modulates the JAK2/STAT3, M1 mAChR, and ERK signaling network...
December 21, 2018: Food & Function
Julia E Pedersen, Christina A Bergqvist, Dan Larhammar
The family of muscarinic acetylcholine receptors (mAChRs) consists of five members in mammals, encoded by the CHRM1 -5 genes. The mAChRs are G-protein-coupled receptors, which can be divided into the following two subfamilies: M2 and M4 receptors coupling to Gi/o ; and M1, M3, and M5 receptors coupling to Gq/11 . However, despite the fundamental roles played by these receptors, their evolution in vertebrates has not yet been fully described. We have combined sequence-based phylogenetic analyses with comparisons of exon-intron organization and conserved synteny in order to deduce the evolution of the mAChR receptors...
September 2018: ENeuro
Na-Ra Lee, Satheesh Gujarathi, Shobanbabu Bommagani, Kiranbabu Siripurapu, Guangrong Zheng, Linda P Dwoskin
Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1 -M5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (Ki  = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1 -M5 mAChRs, respectively. Based on results from the [3 H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs...
December 11, 2018: Bioorganic & Medicinal Chemistry Letters
Manuela Jörg, Emma T van der Westhuizen, Elham Khajehali, Wessel A C Burger, Jonathan M White, Kwok H C Choy, Andrew B Tobin, Patrick M Sexton, Celine Valant, Ben Capuano, Arthur Christopoulos, Peter J Scammells
Targeting allosteric sites of the M1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study...
December 14, 2018: ACS Chemical Neuroscience
Cai-Hong Xiong, Ming-Gang Liu, Lan-Xue Zhao, Mu-Wen Chen, Ling Tang, Ying-Hui Yan, Hong-Zhuan Chen, Yu Qiu
Cognitive flexibility is an important aspect of executive function. The cholinergic system, an important component of cognition, has been shown to modulate cognitive flexibility mainly through the striatum and prefrontal cortex. The role of M1 muscarinic receptors (M1 mAChRs), an important therapeutic target in the cholinergic system, in hippocampus-dependent cognitive flexibility is unclarified. In the present study, we demonstrated that selective activation of M1 mAChRs promoted extinction of initial learned response and facilitated acquisition of reversal learning in the Morris water maze, a behavior test that is mainly dependent on the hippocampus...
December 6, 2018: Neuropharmacology
Yuji Odagaki, Masakazu Kinoshita, Toshio Ota, J Javier Meana, Luis F Callado, Jesús A García-Sevilla
The biochemical abnormalities in transmembrane signal transduction mediated through G protein-coupled receptors (GPCRs) have been postulated as underlying pathophysiology of psychiatric diseases such as schizophrenia and mood disorders. In the present study, the experimental conditions of agonist-induced [35 S]GTPγS binding in postmortem human brain membranes were optimized, and the responses induced by a series of agonists were pharmacologically characterized. The [35 S]GTPγS binding assay was performed in postmortem human prefrontal cortical membranes by means of filtration techniques, and standardized as to GDP concentration, membrane protein content, MgCl2 and NaCl concentrations in assay buffer, incubation period, and effect of white matter contamination...
December 3, 2018: Basic & Clinical Pharmacology & Toxicology
M E Sales, A J Español, A R Salem, P Pulido Martínez, Y Sanchez, F Sanchez
BACKGROUND: Muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies. METHODS: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment...
December 2, 2018: Current Clinical Pharmacology
Naveen Sharma, Eun-Joo Shin, Nam Hun Kim, Eun-Hee Cho, Ji Hoon Jeong, Choon Gon Jang, Seung-Yeol Nah, Toshitaka Nabeshima, Yukio Yoneda, Jean Lud Cadet, Hyoung-Chun Kim
Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the underlying mechanism conveyed by FIR remains unclear. Recently, we demonstrated that exposure to FIR induces antioxidant potentials via up-regulation of glutathione peroxidase (GPx)-1 gene. The antioxidant potentials might be important for the modulation on the neuropsychotoxic conditions. Exposure to FIR protects from methamphetamine (MA)-induced memory impairments via phosphorylation of ERK 1/2 signaling by positive modulation of protein kinase C δ (PKCδ), M1 muscarinic acetylcholine receptor (M1 mAChR), and nuclear factor E2-related factor 2 (Nrf2) transcription factor...
November 27, 2018: Neurochemistry International
Marinela Couselo-Seijas, Jose N López-Canoa, Rosa M Agra-Bermejo, Esther Díaz-Rodriguez, Angel L Fernandez, Jose M Martinez-Cereijo, Dario Durán-Muñoz, Susana B Bravo, Alba Velo, Laila González-Melchor, Xesus A Fernández-López, Jose L Martínez-Sande, Javier García-Seara, Jose R González-Juanatey, Moises Rodriguez-Mañero, Sonia Eiras
Botulinum toxin injection on epicardial fat, which inhibits acetylcholine (ACh) release, reduced the presence of atrial fibrillation (AF) in patients after heart surgery. Thus, we wanted to study the profile of the released proteins of epicardial adipose tissue (EAT) under cholinergic activity (ACh treatment) and their value as AF predictors. Biopsies, explants, or primary cultures were obtained from the EAT of 85 patients that underwent open heart surgery. The quantification of muscarinic receptors (mAChR) by real-time polymerase chain reaction or western blot showed their expression in EAT...
November 27, 2018: Journal of Cellular Physiology
Catherine A Thorn, Joshua Moon, Clinton A Bourbonais, John Harms, Jeremy R Edgerton, Eda Stark, Stefanus J Steyn, Christopher R Butler, John T Lazzaro, Rebecca E O'Connor, Michael Popiolek
Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer's diseases. This is best exemplified by clinical observations with xanomeline, whose efficacy is thought to be mediated through co-activation of the M1and the M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3'-5'-cyclic adenosine monophosphate-response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation, in striatum, hippocampus and prefrontal cortex...
November 27, 2018: ACS Chemical Neuroscience
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